Concentrate for medical solution and use thereof

ABSTRACT

Concentrates are disclosed for use in the preparation of infusion solutions preferably for use in dialysis including gluconic acid and glucose in amounts such that upon dilution with an aqueous solution in a ratio of at least about 1:150, the concentration of the gluconic acid is at least about 600 mmol/l and the concentration of the glucose is at least about 150 g/l.

FIELD OF THE INVENTION

The present invention relates to a concentrate for preparing a medicalsolution, such as a dialysis solution intended for hemodialysis,hemodifiltration, hemofiltration or peritoneal dialysis. Moreparticularly, the present invention relates to a concentrate comprisingglucose and an acid.

BACKGROUND OF THE INVENTION

A concentrate may be a solution in water of one or more substances,which solution is intended to be diluted with water in a desired ratio,such as 1:35.

A concentrate may alternatively be in powder form, for examplecomprising sodium bicarbonate in powder form, which concentrate isintended to be dissolved in water, and then diluted. Such dissolutionmay take place in a separate process, so that all of the powder isdissolved before dilution. The dissolution may also take place on-lineby passing water through a bed of powder in order to produce a solutionto then be diluted. The powder can be a single component, such as sodiumbicarbonate or sodium chloride, or a mixture of components, such assodium chloride, potassium chloride, magnesium chloride, calciumchloride, etc.

It is conventional during hemodialysis to prepare the dialysis solutionin situ by mixing one or more concentrates with water in a dialysismachine. The dialysis machine controls the mixing so that the correctcomposition of the prepared dialysis solution is attained.

A dialysis machine is described in European Application No. 278,100 forthe preparation of a dialysis solution starting from one or moreconcentrates in powder form and one or more concentrates in liquid form.The concentrates are diluted with pure water obtained from a waterpurifier, such as an RO-unit (reverse osmosis unit)

The dialysis machine prepares a dialysis solution comprising sodium,bicarbonate, potassium, calcium, magnesium, chloride and acetate ions insuitable concentrations, as well as possibly glucose and other ions, allbeing dissolved in water. The concentrations of the ions in the dialysissolution are generally mirror images of the corresponding concentrationsin blood, where the mirror line is the normal concentration of the ionsin blood. Thus, if an ion concentration is increased in the blood overthe normal concentration, the ion concentration in the dialysis solutionis decreased in relation to the normal concentration. The pH of thesolution is adjusted to about 7.1 to 7.4. A typical composition of thedialysis solution is the following:

sodium ions 130-150 mM   bicarbonate ions 20-40 mM  potassium ions 2-5mM calcium ions 0-5 mM magnesium ions 0-5 mM glucose 0-0.2% acetate ions3-4 mM (as well as chloride ions)

As is apparent from the above table, in addition to pure water, thereare two substances which are present in the prepared dialysis solutionin large quantities, namely sodium ions and bicarbonate ions. In theabove-mentioned publication, European Application No. 280,100, at leastone of these bulk substances is provided by the machine, starting frompowder concentrate provided in one or more columns.

The remaining substances are supplied from a fluid concentrate whichprimarily comprises potassium, calcium and magnesium ions, and possiblyglucose. This concentrate further comprises an acid to balance the pHvalue for the bicarbonate so that the final dialysis solution has aphysiological pH value of about 7.1 to 7.4. Normally, acetic acid(acetate ions) is used. Since these substances are present in relativelysmall quantities, the solution can be very concentrated.

A concentrate is described in European Application No. 613,688 having adegree of concentration of between about 1:120 and 1:250, i.e. it isintended to be diluted with water in that ratio. It is said to comprisesodium chloride, potassium chloride, calcium chloride, magnesiumchloride, hydrochloric/acetic acid and glucose. The concentrate is to becombined with a basic concentrate, which comprises the two substanceswhich are present in large quantities, namely sodium and bicarbonateions, derived from sodium chloride, and sodium bicarbonate. Moreover,the basic concentrate comprises sodium acetate. Sodium acetate isdescribed as being mixed in the basic concentrate because the additionof sodium acetate prevents precipitation of bicarbonate by complexformation between acetate and bicarbonate ions. The highly concentratedconcentrate is used as a treatment individualisation concentrate. Thisis possible since the concentrate is used in small quantities, normallyless than about one liter per treatment. Many different compositions ofthe individualisation concentrate can be stored in a limited storagespace. The highly concentrated concentrate has a very high saltconcentration (ionic strength) and is viscous.

During experimentation with a highly concentrated concentrate having adegree of concentration of 1:400, comprising, among other things,glucose and 1200 mM (mmole/liter) acetic acid (undiluted), we discoveredthat, after one week's storage, the acetate ion concentration wasreduced markedly; i.e., by more than 5%. Accordingly, the concentratedid not comply with the information on the label that it contained 3 mM(mmol/l) acetate after dilution in the ratio of 1:400 and with a marginof error of ±5%. In addition, the reduction in the acetic concentrationindicated that some other substance had formed, probably by reactionwith, or through decomposition of, glucose. Such substance may have aninfluence upon the patient who is undergoing dialysis.

During continued experiments, it appeared that there is probably aninteraction or reaction between acetic acid and glucose causing thereduction in acetate concentration and also of glucose concentration.Accordingly, the concentration of acid was reduced during storage, whichmay result in raising the pH value of the final prepared solution to anunacceptable level.

The concentration values which are present in the concentrate are about1.2 M acetic acid (or another acid) and about 2.2-4.4 M glucose at aconcentration of 1:400, which results in 3 mM acetic acid and 0.1-0.2%glucose in the finally prepared dialysis solution.

One object of the present invention is to provide a concentrate fordilution with a medical solution, in which the acid concentration is notreduced during storage.

Another object of the present invention is to provide a concentrate fora medical solution which lacks acetate ions, since a great number ofpatients have developed intolerance to acetate ions.

Yet another object of the present invention is to provide a concentratefor a medical solution, comprising a physiologically acceptable aid forreplacing the conventionally used acetic acid.

SUMMARY OF THE INVENTION

In accordance with the present inventions, these and other objects havenow been realized by the invention of a concentrate for use in thepreparation of an infusion solution comprising gluconic acid and glucosein amounts such that upon dilution with an aqueous solution in a ratioof at least about 1:150 the concentration of the gluconic acid is atleast about 600 mmol/l and the concentration of the glucose is at leastabout 150 g/l. In a preferred embodiment, the gluconic acid and glucoseare present in amounts such that upon dilution with an aqueous solutionin a ratio of at least about 1:200 the concentration of the gluconicacid is at least about 800 mmol/l and the concentration of the glucoseis at least about 200 g/l. In a most preferred embodiment, the gluconicacid and glucose are present in amounts such that upon dilution with anaqueous solution in a ratio of at least about 1:400, the concentrationof the gluconic acid is at least about 1600 mmol/l and the concentrationof the glucose is at least about 400 g/l.

In accordance with a preferred embodiment of the concentrate of thepresent invention, the infusion solution comprises a dialysis solutionfor use in hemodialysis, hemodiafiltration, hemofiltration or peritonealdialysis.

In accordance with another preferred embodiment of the concentrate ofthe present invention, the concentrate is substantially free of acetateions.

In accordance with one embodiment of the concentrate of the presentinvention, the concentrate includes sufficient water to provide aninfusion solution in a ratio of at least about 1:150. Preferably, theconcentrate includes sufficient water to provide an infusion solution ina ratio of at least about 1:200.

In accordance with another embodiment of the concentrate of the presentinvention, the gluconic acid is provided in the concentrate bydissolving powdered glucono-lactone in water.

During experimentation with other acids, we have thus discovered, quitesurprisingly, that the abovementioned reduction of the acetic acid andglucose concentrations does not occur if gluconic acid is used insteadof acetic acid. More or less the same effect also occurs with othersaccharic acids such as glycuronic acid, glucaric acid, etc. The sameeffect can also be attained from sodium gluconate together withhydrochloric acid, due to the fact that gluconic acid is formed by thereaction of sodium gluconate and hydrochloric acid. Gluconic acid(C₆H₁₂O₇) can also be obtained by dissolving gluconolactone (C₆H₁₀O₆) inwater, as described further below.

In accordance with the present invention, by replacing theconventionally used acetic acid, which contains acetate ions, withgluconic acid, even patients with acetate ion intolerance can be treatedwith a medical solution obtained according to this invention.

Gluconic acid has previously been used in connection with peritonealdialysis, see European Patent No. 612,528, as an osmotic agent, i.e. as(partial) replacement for glucose. In that European patent, it isdisclosed that gluconic acid can totally or partially replace glucose,i.e. mixtures of gluconic acid and glucose are used. Thoseconcentrations which are mentioned are between 75 and 250 mM of theadded or combined concentrations of gluconic acid and glucose.

In the present invention, the demonstrated effect of reduction of theacetic acid and glucose concentrations arises at considerably higherconcentrations. Thus, at a degree of concentration of 1:400, thecombined concentrations of glucose and gluconic acid are from about 3.4to 5.6 M. At 250 mM, the effect according to the present invention ishardly detectable. Nowhere in European Patent No. 612,528 is itmentioned that gluconic acid should have any favorable effect on thestability of glucose.

Gluconic acid is a substance which is present in the body and may bedecomposed in the body. Accordingly, it should not cause any damage orbe accumulated in the body.

Gluconic acid is a somewhat stronger acid than acetic acid. In order tothus have the same effect as 3 mM acetic acid, referred to as thediluted dialysis solution, a somewhat higher concentration of gluconicacid is therefore necessary, such as from about 4 to 5 mM, probablyprimarily due to formation of lactones which are converted to gluconicacid at an acceptable rate only when the pH value reaches about 9.

Accordingly, there is provided, according to the present invention, aconcentrate for use in the preparation of an infusion solution or amedical solution for hemodialysis, hemodiafiltration, hemofiltration orperitoneal dialysis, comprising gluconic acid. The concentrate mayfurther comprise glucose.

Gluconic acid may replace the conventional use of acetic acid, whichmeans that a concentrate could be produced which lacks acetate ions.

The concentrate is intended to be diluted with water or an aqueoussolution in a ratio of at least about 1:150 and comprises at least about150 g/l glucose and at least about 600 mmol/l gluconic acid.

The present invention also comprises the use of a concentrate comprisinggluconic acid and glucose for the preparation of a medical infusionsolution, whereby the solution is diluted with water in a ratio of atleast 1:150.

According to another aspect of the present invention, it comprises useof a concentrate comprising gluconic acid and possibly glucose, for thepreparation of a medical solution intended for hemodialysis,hemodifiltration, hemofiltration or peritoneal dialysis, whereby theconcentrate is diluted with water and mixed with a solution comprisingsodium bicarbonate and in which gluconic acid is used to adjust themedical solution to a physiological pH value of between about 7.1 and7.4.

The present invention will be described in more detail below withreference to the following detailed description which, in turn, refersto the attached drawings. Further objects, features and advantages ofthe present invention will thus be apparent from the followingdescription.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graphical representation in which the reduction inconcentration is shown as a function of time for different degrees ofconcentration and at different temperatures;

FIG. 2 is a graphical representation in which the concentration ofgluconic acid is shown as a function of time for different degrees ofconcentration and with and without glucose;

FIG. 3 is a graphical representation in which the concentration ofgluconic acid is shown as a function of time for different degrees ofconcentration and with and without glucose;

FIG. 4 is a graphical representation in which the concentration ofgluconic acid is shown as a function of time for different degrees ofconcentration and with and without glucose;

FIG. 5 is a graphical representation in which the concentration ofgluconic acid is shown as a function of time for different degrees ofconcentration and with and without glucose;

FIG. 6 is a graphical representation in which the concentration ofgluconic acid is shown as a function of time for different degrees ofconcentration and with and without glucose; and

FIG. 7 is a graphical representation in which the concentration ofgluconic acid is shown as a function of time for different degrees ofconcentration and with and without glucose.

DETAILED DESCRIPTION

FIG. 1 is a diagram which includes a summary of the results ofExperiments 1-10, as follows:

EXPERIMENTS 1, 2 AND 3

We have analyzed previously manufactured concentrates of a normalcomposition for hemodialysis and having the following intendedcomposition after dilution:

sodium 140 mM potassium  2 mM calcium 1.75 mM  magnesium  0.5 mM glucose0.1% or 0.2% acetate ions 3 or 4 mM  

In the absence of any indications to the contrary, all of theseconcentration values refer to the concentration values in the finallydiluted solution. The concentration values in the above disclosedconcentrate are thus 35 times greater than the given values. In thismanner, it is easier to compare concentrates with different degrees ofconcentration which are intended to result in the same concentration inthe final solution.

These concentrates had been stored for 3.5 years and were analyzed forthe concentration of acetic acid. The measurement points in the diagramare marked with a solid triangle for Experiment 1: 0.1% glucose, 3 mMHAc, a hollow triangle for Experiment 2: 0.2% glucose, 3 mM HAc and ahollow square for Experiment 3: 0.2% glucose, 4 mM HAc.

As is apparent from FIG. 1, the concentration of acetic acid isunchanged at 0.1% glucose and reduced at 0.2% glucose, to the extent ofjust under 2% at the maximum. These measured values lie within thetolerance limits for such concentrates and may be caused by differencesduring manufacture. We were unable to test these concentrates forshorter storage periods. However, we surmise that the deviations fromthe initial values would be less if the concentrates were stored for ashorter period.

EXPERIMENTS 4 AND 5

We have also analyzed liquid concentrates with the above-describedcomposition, but without the sodium chloride, in the case where sodiumchloride is produced by the dialysis machine starting from a powderconcentrate. We have tested two different degrees of concentration,namely 1:175 in Experiment 4 and 1:350 in Experiment 5. The concentrateshad the following composition, multiplied by 175 and 350, respectively:

potassium 2 mM calcium 1.75 mM   magnesium 0.5 mM   glucose 0.1% acetateions 3 mM

The 1:175 and 1:350 concentrates were tested after 2 years of storage,and the result is illustrated in FIG. 1, using a diamond for Experiment4, 1:175, and a hollow dotted square for Experiment 5, 1:350. As isclearly apparent, the reduction in the acetic acid concentration for theconcentration 1:175 is about 3%, which is within the tolerance limits.For the double concentration 1:350, there is a reduction of about 9%,which is outside of the tolerance limits.

EXPERIMENTS 6, 7, 8 AND 9

We have performed a test series with concentrates having degrees ofconcentration of 1:200 and 1:400 which were manufactured andcontinuously monitored during a period of just over one year. Theconcentrates had the same composition as those used for experiments 4and 5, except that they were multiplied with the given degrees ofconcentration.

The 1:200 concentrate in Experiment 6, denoted on FIG. 1 by soliddiamonds, demonstrates a continuous reduction of the acetic acidconcentration that seems to level out at a reduction of just below 4%.

The same applies for two experiments; namely, Experiment 7, indicated byhollow small squares, and Experiment 8, indicated by filled smallsquares, with the same composition but aged in a climatic chamber at 40°C. As is apparent from FIG. 1, Experiments 7 and 8 reach equilibrium ata reduction of about 4% after about 2 months. The curve of Experiment 7was obtained by means of titration and the curve of Experiment 8 wasobtained by HPLC chromatography. The differences lie within the errortolerances of the methods.

We have also manufactured a concentrate with a degree of concentrationof 1:400, Experiment 9 indicated by hollow squares with a dot, which wasfollowed for slightly more than one year. Here the situation, asillustrated in FIG. 1, is quite clear, namely that the acetic acidconcentration reduces rapidly during the first weeks and then levels outat a reduction of about 10.5%.

EXPERIMENT 10

We have also performed experiments with concentrates without glucosehaving a degree of concentration of 1:400. As is apparent from FIG. 1,where Experiment 10 is indicated by crosses, no marked reduction ofacetic acid concentration is detected.

The combined observations from the various experiments is quite clear.The acetic acid concentration reduces in all concentrates. The reductionis dependent on the degree of concentration of the solution. This effecthas not been observed in the literature.

We have also been able to determine that the glucose concentrationreduces in proportion to the reduction of the acetic acid concentration.This causes us to assume that the acetic acid reacts with glucose andforms a reaction product.

We have unexpectedly discovered that if the acetic acid is replaced bygluconic acid, the above reduction of the acid concentration and theglucose concentration is not observed, as can be seen in the followingexperiments.

FIGS. 2-8 are diagrams of the concentration of gluconic acid and the pHvalues, respectively, for concentrates with the following composition:

potassium 2 mM calcium 1.75 mM   magnesium 0.5 mM   glucose 0% or 0.1%gluconic acid 4 mM

EXPERIMENTS 11 AND 12

In experiments 11 and 12, FIGS. 2 and 3, a concentrate with a degree ofconcentration of 1:35, i.e. a “conventional” concentrate, was used. Theconcentrate further comprises sodium chloride with a concentration of140 mM (times 35). Experiment 11 is without glucose and experiment 12 iswith 0.1% glucose. Two parallel trial series are run, one in which theconcentrates are stored at 25° C. and the other in which theconcentrates are stored at 40° C. Since ageing takes place more quicklyat higher temperatures, a difference between the two concentrates shouldquickly arise if any reaction takes place.

As is seen from FIGS. 2 and 3, no differences are observed. Theconcentration of the gluconic acid was measured by means of titration(square and diamond denoted by M/25C and M40C in FIGS. 2 and 3) and bymeasurement of the pH value (triangle and cross denoted by pH/25C andpH/40C in FIGS. 2 and 3). As is apparent from FIGS. 2 and 3, theconcentration of gluconic acid is constant at about 0.105 M.Furthermore, the pH value is relatively constant at pH=1.6. Thevariations which are apparent in FIGS. 2 and 3, and also from thefollowing diagrams, are believed to be due to calibration of the pHmeter.

EXPERIMENTS 13 AND 14

As illustrated in FIGS. 4 and 5, the same experiments were performed asin experiments 11 and 12, with a degree of concentration of 1:200 andwithout sodium chloride.

It is apparent from these figures that no change occurs in theconcentration of gluconic acid which is constant at 0.6 M. The pH valuesare also relatively constant.

EXPERIMENTS 15 AND 16

As illustrated in FIGS. 6 and 7, the same experiments were performed asin experiments 13 and 14, with a degree of concentration of 1:400.

Again, it is apparent from the diagrams that substantially no changeoccurs in the concentration of gluconic acid which is constant at 1.2 M(undiluted). The pH values are also relatively constant.

It is to be noted that the pH value in FIG. 7, where glucose is added,is clearly lower than in FIG. 6, without glucose. We believe that thisdifference is not an actual difference but instead is due to glucoseaffecting the pH electrode. As is apparent, the titrated concentration(M) is constant and of the same magnitude in FIGS. 6 and 7.

Our measurements over a long period and documented in Experiments 11-16show that the gluconic acid retains a stable concentration and does notappear to react with glucose. Accordingly, both the acid concentrationand the glucose concentration are retained.

It should be noted that a somewhat greater quantity of gluconic acid isrequired as compared to acetic acid in order to obtain the same effectwhen mixing a dialysis solution starting from concentrates.

We have not been able to find any reason to suspect that anyunidentified substance is produced which may have potentially damagingeffect on a patient who is treated using this concentrate (afterdilution) during dialysis or infusion.

Gluconic acid can be obtained on the market in the form of 50% solution.However, we prefer to use glucono-delta-lactone (C₆H₁₀O₆) which can beobtained in powder form and in pure form. When dissolved in water,gluconolactone is substantially immediately hydrolysed to gluconic acid.

Gluconic acid is naturally occurring in the body. We have been unable toevidence any damaging effect on the body from the use of gluconic acidduring dialysis.

According to the present invention, the conventionally used acetic acidis replaced by gluconic acid. The gluconic acid, or more preciselygluconate, can also act as a buffer, and thus replace lactate duringperitoneal dialysis.

Gluconic acid can also be produced in situ by mixing sodium gluconatewith hydrochloric acid, whereby gluconic acid is formed. It is alsopossible to use other salts comprising gluconate, such as potassiumgluconate, calcium gluconate and magnesium gluconate, since thesecations, potassium, calcium and magnesium ions, normally are included ina dialysis solution. In other types of solutions, other salts may beused.

Although the invention herein has been described with reference toparticular embodiments, it is to be understood that these embodimentsare merely illustrative of the principles and applications of thepresent invention. It is therefore to be understood that numerousmodifications may be made to the illustrative embodiments and that otherarrangements may be devised without departing from the spirit and scopeof the present invention as defined by the appended claims.

What is claimed is:
 1. A concentrate for use in the preparation of adialysis solution comprising gluconic acid and glucose in amounts suchthat upon dilution with an aqueous solution in a ratio of at least about1:150 the concentration of said gluconic acid is at least about 600mmol/l and the concentration of said glucose is at least about 150 g/l.2. A concentrate for use in the preparation of a dialysis solutioncomprising gluconic acid and glucose in amounts such that upon dilutionwith an aqueous solution in a ratio of at least about 1:200 theconcentration of said gluconic acid is at least about 800 mmol/l and theconcentration of said glucose is at least about 200 g/l.
 3. Aconcentrate for use in the preparation of a dialysis solution comprisinggluconic acid and glucose in amounts such that upon dilution with anaqueous solution in a ratio of at least about 1:400 the concentration ofsaid gluconic acid is at least about 1600 mmol/l and the concentrationof said glucose is at least about 400 g/l.
 4. A concentrate according toclaim 1, 2 or 3 wherein said dialysis solution comprises a dialysissolution for use in hemodialysis, hemodiafiltration, hemofiltration orperitoneal dialysis.
 5. The concentrate of claim 1, 2 or 3 substantiallyfree of acetate ions.
 6. The concentrate of claim 1 including sufficientwater to provide a dialysis solution in a ratio of at least about 1:150.7. The concentrate of claim 6 including sufficient water to provide adialysis solution in a ratio of at least about 1:200.
 8. The concentrateof claim 1 wherein said gluconic acid is provided in said concentrate bydissolving powdered glucono-lactone in water.